Isoquinoline compounds

Patent metadata

Field	Value
Publication number	US-9624195-B2
Application number	US-201514998131-A
Country	US
Kind code	B2
Filing date	Dec 23, 2015
Priority date	Dec 24, 2014
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

Described herein are compounds of Formula (I) and tautomers and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.

First claim

What is claimed is:

1. A compound of Formula I:

or a tautomer or pharmaceutically acceptable salt thereof, wherein
X 1 , X 2 , X 3 , and X 4 are each independently C(R 7 ) or N, wherein 0 to 2 of X 1 , X 2 , X 3 , and X 4 are N;
R 1 is —H, —CN, —OR a , C 1-6 haloalkyl or halogen;
R 2 is —H, —NR b R c , —SR a , —OR a or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different;
R 3 and R 4 are each independently —H, —OR a , halogen, —NR b R c , —C(O)OR a , —CN, —C(O)NR b R c , —NHC(O)NR b R c , —OC(O)NR b R c , CH 2 C(O)NR b R c , C 1-6 alkyl or C 1-6 heteroalkyl, wherein each C 1-6 alkyl or C 1-6 heteroalkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different;
R 5 and R 6 are each independently halogen, —OR a or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different;
each R 7 is independently —H, halogen, —OR a or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different;
each R 8 is independently C 1-6 alkyl, C 1-6 heteroalkyl, aryl, heteroaryl, halogen, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR b R c , —OC(O)NR b R c , —NR b C(O)OR a , —SR a , —S(O) 1-2 R a , —S(O) 2 F, —S(O) 2 NR b R c , —NR b S(O) 2 R a , —N 3 , —CN or —NO 2 , wherein each C 1-6 alkyl, C 1-6 heteroalkyl, aryl or heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 halogen, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR b R c , —OC(O)NR b R c , —NR b C(O)OR a , —SR a , —S(O) 1-2 R a , —S(O) 2 F, —S(O) 2 NR b R c , —NR b S(O) 2 R a , —N 3 , —CN or —NO 2 groups, which may be the same or different;
each R a is independently —H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R 21 groups, which may be the same or different;
R b and R c are each independently —H, —NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, aryl or heteroaryl, wherein each C 1-6 alkyl, C 1-6 heteroalkyl, aryl or heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R 21 groups; or R b and R c together with the atoms to which they are attached form a C 1-10 heterocycloalkyl;
R 21 is C 1-6 alkyl, —CN, aryl, heteroaryl or halogen.

2. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 is —H, —NR b R c or —OH.

3. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 is —H, —NH 2 or —OH.

4. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently —H, —OR a , halogen, —NR b R c , —C(O)OR a , or —C(O)NR b R c .

5. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each —H.

6. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

or a tautomer or pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein

is selected from

8. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ib:

or a tautomer or pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein

is

10. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are each independently halogen, —O—C 1-6 alkyl or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different.

11. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is —H, —CN, —O—C 1-6 alkyl, —CF 3 , —O—C 1-3 haloalkyl or halogen.

12. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 —CN.

13. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein each R 7 is independently —H, halogen, —O—C 1-6 alkyl or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R 8 groups, which may be the same or different.

14. The compound of claim 1 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein each R 7 is —H.

15. The compound of claim 1 , wherein the compound is selected from

or a tautomer or pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 , further comprising at least one or more additional therapeutic agents.

18. The pharmaceutical composition of claim 17 , wherein the at least one or more additional therapeutic agents is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

19. A method of inhibiting reverse transcriptase in a subject in need thereof, comprising administering a compound of claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, to the subject.

20. A method for treating an HIV infection in a subject comprising administering to the subject a compound of claim 1 , or a tautomer or pharmaceutically acceptable salt thereof.

21. A method for treating an HIV infection in a subject comprising administering to the subject in need thereof a compound of claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents independently selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

Assignees

• Gilead Sciences Inc

Inventors

• Hu Yunfeng Eric
• Jansa Petr
• Lansdon Eric
• Mackman Richard L

Classifications

• A61P31/18

  for HIV · CPC title

• C07D217/22 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/472

  Non-condensed isoquinolines, e.g. papaverine · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title